Interstate 35 (I-35) is a north–south Interstate Highway in the United States that runs from Laredo, Texas, to Duluth, Minnesota. In Iowa, the highway runs from south to north through the center of the state, roughly parallel to U.S. Highway 69 (US 69) and US 65. It enters the state near Lamoni from Missouri and continues north through the southern Iowa drift plain. In the Des Moines area, I-35 runs concurrently with I-80, and the two highways bypass Des Moines to the west and north. I-235, the only auxiliary route of I-35, serves the suburbs and downtown Des Moines; it begins and ends at the two interchanges where I-35 and I-80 meet. Near Mason City and Clear Lake, US 18 and Iowa Highway 27 (Iowa 27) overlap with I-35. Shortly after, US 18 splits off to the west in Clear Lake, while Iowa 27 runs with I-35 until they reach the Minnesota state line.

Interstate 80 (I-80) is a transcontinental Interstate Highway in the United States, stretching from San Francisco, California, to Teaneck, New Jersey. In Iowa, the highway travels west to east through the center of the state. It enters the state at the Missouri River in Council Bluffs and heads east through the southern Iowa drift plain. In the Des Moines metropolitan area, I-80 meets up with I-35 and the two routes bypass Des Moines together. On the northern side of Des Moines, the Interstates split and I-80 continues east. In eastern Iowa, it provides access to the University of Iowa in Iowa City. Northwest of the Quad Cities in Walcott is Iowa 80, the world's largest truck stop. I-80 passes along the northern edge of Davenport and Bettendorf and leaves Iowa via the Fred Schwengel Memorial Bridge over the Mississippi River into Illinois.